Abstract: In our long-term studies on Natural History of Microalbuminuria (MA) in type 1 diabetes we found that in the majority of patients MA regresses to normo-albuminuria, However, in a third of patients with MA significant renal function decline occurs; this decline is progressive and appears to be launched at the onset of MA. Because renal function at the onset of MA is in the normal or elevated range, we call this phenomenon early renal function decline (ERFD). Once initiated, ERFD progresses until significant renal function impairment is reached with subsequent development of ESRD. In this renewal we aim to study etiology of ERFD and find diagnostic tools for it. This proposal has the following specific aims: 1) To continue the follow-up of the cohort of 935 patients recruited into the 2nd Joslin Study on the Natural History of MA in T1DM. Extended follow-up measurements of cystatin C will provide critical precision to determinations of the rate of renal function loss in these patients and at the same time the prospective measurements of biomarkers in serum and urine will provide data for the examination of hypotheses about the mechanisms underlying initiation and promotion of ERFD; 2) To examine in the extended study the associations of serum uric acid and serum biomarkers of inflammation (TNF, sTNFR-1, sTNFR-2, sFas, IP-10 and ICAM) with the risk of ERFD; 3) To examine in the extended study the associations of various biomarkers excreted in urine with the risk of ERFD. The following urinary biomarkers will be studied: a) Albumin, IgG2 and IgA - biomarkers of glomerular filtration barrier damage, b) NAG and Kim-1 - biomarkers of proximal tubule damage and c) MCP-1, IL-8, IP- 10, VCAM, sTNFR-1, and sTNFR-2 - biomarkers of inflammation in the kidney. 4) To determine whether the 21 genomic regions and genes identified by the leading SNPs associated with ERFD in the whole genome association study (WGAS) performed in the 1st Joslin Study are replicated in the 2nd Joslin Study samples. 5) To design a diagnostic protocol (analogous to the Framingham score for the assessment of risk of CAD) that combines clinical predictors with serum, urinary, and genetic biomarkers for ERFD, so that ERFD can be diagnosed early in the course of disease (within 1-2 years of observation instead of 4-8 years). The Joslin Clinic is a unique and ideal setting that makes this proposal feasible. The success of the proposal is further assured because we have already recruited and examined 935 patients with T1DM and MA, implemented the protocols required for this research, demonstrated our ability to continuously follow these patients and analyzed preliminary data and developed several new exiting hypothesis about etiology of ERFD.